Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

Abstract

Post-prandial hyperlipidemia has emerged as a cardiovascular risk factor with limited therapeutic options. The Liver X receptors (Lxrs) are nuclear hormone receptors that regulate cholesterol elimination. Knowledge of their role in regulating the absorption and handling of dietary fats is incomplete. The purpose of this study was to determine the role of intestinal Lxrα in post-prandial intestinal lipid transport. Using Lxrα knockout (nr1h3−/−) and intestine-limited Lxrα over-expressing [Tg(fabp2a:EGFP-nr1h3)] zebrafish strains, we measured post-prandial lipid excursion with live imaging in larvae and physiological methods in adults. We also conducted a long-term high-cholesterol dietary challenge in adults to examine the chronic effect of modulating nr1h3 gene dose on the development of hypercholesterolemia and hepatic lipid accumulation. Over-expression of Lxrα in the intestine delays the transport of ingested lipids in larvae, while deletion of Lxrα increases the rate of lipid transport. Pre-treating wildtype larvae with the liver-sparing Lxr agonist hyodeoxycholic acid also delayed the rate of intestinal lipid transport in larvae. In adult males, deletion of Lxrα accelerates intestinal transport of ingested lipids. Adult females showed higher plasma Lipoprotein lipase (Lpl) activity compared to males, and lower post-gavage blood triacylglycerol (TAG) excursion. Despite the sexually dimorphic effect on acute intestinal lipid handling, Tg(fabp2a:EGFP-nr1h3) adults of both sexes are protected from high cholesterol diet (HCD)-induced hepatic lipid accumulation, while nr1h3−/− mutants are sensitive to the effects of HCD challenge. These data indicate that intestinal Lxr activity dampens the pace of intestinal lipid transport cell-autonomously. Selective activation of intestinal Lxrα holds therapeutic promise.

HDL cholesterol protects from liver injury in mice with intestinal specific LXRα activation

“…Unfortunately, the use of LXR ligands, which enhance HDL synthesis and regulate cholesterol homeostasis, is not practicable because systemic activation of LXRs may cause side effects because of LXRα induction in hepatocytes and consequent hepatic steatosis and hypertriglyceridemia. Accordingly to previous evidence, 18,35,36 our data confirms that the specific intestinal activation of LXRα could be an actionable pathway without modifying hepatic lipid metabolism 37 …”

“…Accordingly to previous evidence, 18,35,36 our data confirms that the specific intestinal activation of LXRα could be an actionable pathway without modifying hepatic lipid metabolism. 37 In conclusion, we showed that intestinal LXRα activation increases HDL levels and exerts anti-inflammatory and anti-oxidant effects on hepatic macrophages and parenchymal cells, finally ameliorating hepatic response to chronic injury (Figure 8). Hence, approaches that point to increase the HDL production, via intestinal LXRα activation, may represent new strategies for the treatment of chronic liver diseases.…”

Modeling hypercholesterolemia and vascular lipid accumulation in LDL receptor mutant zebrafish

“…The goal of this work was to establish a genetic model of hypercholesterolemia in zebrafish. The ldlr mutant zebrafish developed in this study adds to the set of zebrafish models of lipid abnormalities and lipoprotein oxidation, which includes apoc2 mutant zebrafish that develop severe hypertriglyceridemia (13), loss and gain of function liver X receptor mutants (29,30), and hsp70:IK17-EGFP zebrafish that serve as a reporter for oxidation-specific epitopes (20), among others. We have previously been able to achieve hypercholesterolemia in WT zebrafish by feeding larvae an HCD for 2 weeks, which resulted in accumulation of vascular lipid deposits (14).…”

NPC1L1 inhibition disturbs lipid trafficking and induces large lipid droplet formation in intestinal absorptive epithelial cells

“…of Pathology and Laboratory Medicine, University of Cincinnati, OH, USA). 9, 10(n)-3 H-oleic acid (specific activity, 45.5 Ci/mmol) and [4][5][6][7][8][9][10][11][12][13][14] C]-cholesterol (specific activity, 49.8 mCi/mmol) were purchased from GE Healthcare (Piscataway, NJ, USA). 1-14 C-oleic acid was obtained from…”

“…Similarly, such a post-prandial TAG surge was observed in mice with greater intestinal cholesterol absorption efficiency in mice disrupted for cholesterol efflux transporters, ATP-binding cassette G5/G8 [9]. Moreover, activation of liver X receptor attenuated cholesterol absorption, stimulated lipid droplet formation, and retarded TAG transport in the intestine of Zebra fish [10,11]. On the other hand, cholesterol depletion by statins or an acyl-CoA acyltransferase (ACAT) inhibitor in lipoprotein-producing cell lines, Caco-2 and HepG2 cells, accelerated apolipoprotein (apo) B degradation [12,13].…”